This invention relates to antigestagenically active steroids with a fluorinated 17xcex1-alkyl chain, process for their production, pharmaceutical preparations that contain the latter and their use for the production of pharmaceutical agents.
The invention relates to 17xcex1-fluoroalkyl steroids of general formula I 
in which
R1 stands for a methyl or ethyl group,
R2 stands for a radical of formula CnFmHo, whereby n is 2, 3, 4, 5 or 6, m greater than 1 and m+o=2n+1,
R3 stands for a free, etherified or esterified hydroxy group,
R4 and R5 each stand for a hydrogen atom, or together for an additional bond or a methylene group,
St stands for a steroidal ABC-ring system of partial formula A, B or C 
in which
R6 means a hydrogen atom, a straight-chain C1-C4 alkyl group or branched C3-C4 alkyl group or a halogen atom,
R7 means a hydrogen atom, a straight-chain C1-C4 alkyl group or a branched C3-C4 alkyl group, or
if St stands for a steroidal ABC-ring system A or B, in addition
R6 and R7 together can mean an additional bond,
X means an oxygen atom, a hydroxyimino grouping=Nxe2x80x94OH or two hydrogen atoms,
R8 means a radical Y or an aryl radical that is optionally substituted with Y, whereby Y is a hydrogen atom, a halogen atom, an xe2x80x94OH, xe2x80x94NO2, xe2x80x94N3, xe2x80x94CN, xe2x80x94NR9aR9b, xe2x80x94NHSO2R9, xe2x80x94CO2R9, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkanoyloxy, benzoyloxy, C1-C10 alkanoyl, C1-C10 hydroxyalkyl or benzoyl group, and R9a and R9b are the same or different and represent a hydrogen atom or a C1-C10 alkyl group, R9 is a hydrogen atom or C1-C10 alkyl,
and for xe2x80x94NR9aR9b radicals, as well as their physiologically compatible salts with acids and for xe2x80x94CO2R9 radicals with R9 meaning hydrogen, as well as their physiologically compatible salts with bases.
The wavy lines mean that the substituent in question can be in xcex1- or xcex2-position.
In the alkyl groups that are mentioned within the scope of this invention, these are the methyl, ethyl, n- or iso-propyl, n-, iso- or tert-butyl groups, for example.
The other C1-C10 alkyl groups, Y, R9, R9a, R9b, have the higher homologues in addition, such as, for example, the pentyl, neo-pentyl, hexyl to decyl groups, for example.
C1-C10 alkyl groups are to be understood to encompass, however, carbocyclic or alkylcycloalkyl groups as well with up to 10 carbon atoms, for example the cyclopropyl, cyclopentyl, cycloheptyl, methylcyclopropyl, methylcyclopentyl or methylcyclohexyl radical. A methyl or ethyl group is preferred for all cases above.
C1-C10 alkoxy groups are the radicals that are lengthened by one oxygen atom and derived from the alkyl groups that are mentioned above, thus, e.g., the methoxy, ethoxy, n- or iso-propoxy, n-, iso- or tert-butoxy radical.
C1-C10 alkanoyl is defined as the acyl radicals of straight-chain and branched C1-C10 alkanecarboxylic acids, thus, for example, the formyl, acetyl, propionyl, butyryl or iso-butyryl radical, etc.
C1-C10 Alkanoyloxy radicals are the radicals of the above alkanoyl radicals that are lengthened by one oxygen atom, thus, e.g., the acetyloxy, propionyloxy, and butyryloxy radical.
If a halogen atom is mentioned as a substituent, this can be a fluorine, chlorine or bromine atom. Fluorine is preferred.
For radicals R2, perfluorinated side chains of length n=2-4 are to be preferred and among the latter, in turn the pentafluoroethyl unit is especially to be preferred.
R3 stands primarily for a free hydroxy group.
In the case of an etherified or esterified hydroxy group as a 17xcex2-substituent, the latter is preferably etherified with a C1-C10 alkyl group or esterified with a C1-C10 alkanoyl group. For this alkyl or alkanoyl group, the same meanings as above hold true. The etherification or esterification of the hydroxy group is carried out according to the methods that are familiar to one skilled in the art.
R4 and R5 preferably each stand for a hydrogen atom or together for an additional bond.
If R8 is a group Y, this is preferably a C1-C10 alkanoyl or (1-hydroxy)-C1-C10 alkyl group, whereby among these radicals, the acetyl and the propionyl group are especially to be preferred.
Preferred carbocyclic or heterocyclic aryl radicals are phenyl, 1- or 2-naphthalinyl, 2- or 3-furanyl, 2- or 3-benzofuranyl, 2- or 3-thienyl, 2-, 3- or 4-pyridinyl. As substituted aryl radical R8 (e.g., substituted one or up to several (e.g., 2-3) times with Y), primarily 4-cyanophenyl and a 4-halophenyl radical, especially the 4-fluorophenyl radical, can be cited.
Among all the radicals that are mentioned as preferred for R8, R8 in the meaning of Y and Y in turn equal to acetyl is especially to be preferred.
The compounds that are mentioned below are especially preferred according to the invention:
11xcex2-(4-Acetylphenyl)-17xcex2-hydroxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)estr-4-en-3-one;
4xe2x80x2-[17xcex2-hydroxy-3-oxo-17xcex1-(1,1,2,2,2-pentafluoroethyl)estr-4-en-11xcex2-yl][1,1xe2x80x2-biphenyl]-4-carbonitrile;
11xcex2-(4xe2x80x2-fluoro[1,1xe2x80x2-biphenyl]-4-yl)-17xcex2-hydroxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)estr-4-en-3-one;
17xcex2-hydroxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)-11xcex2-[4-(3-pyridinyl)phenyl]estr-4-en-3-one;
11xcex2-(4-acetylphenyl)-17xcex2-hydroxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)estra-4,15-dien-3-one;
4xe2x80x2-[17xcex2-hydroxy-3-oxo-17xcex1-(1,1,2,2,2-pentafluoroethyl)estra-4,15-dien-11xcex2-yl][1,1xe2x80x2-biphenyl]-4-carbonitrile;
11xcex2-(4xe2x80x2-fluoro[1,1xe2x80x2-biphenyl]-4-yl)-17xcex2-hydroxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)estra-4,15-dien-3-one;
17xcex2-hydroxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)-11xcex2-[4-(3-pyridinyl)phenyl]estra-4,15-dien-3-one;
11xcex2-(4-acetylphenyl)-17xcex2-hydroxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)estra-4,9-dien-3-one;
4xe2x80x2-[17xcex2-hydroxy-3-oxo-17xcex1-(1,1,2,2,2-pentafluoroethyl)estra-4,9-dien-11xcex2-yl][1,1xe2x80x2-biphenyl]-4-carbonitrile;
11xcex2-(4xe2x80x2-fluoro[1,1xe2x80x2-biphenyl]-4-yl)-17xcex2-hydroxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)estra-4,9-dien-3-one;
17xcex2-hydroxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)-11xcex2-[4-(3-pyridinyl)phenyl]estra-4,9-dien-3-one;
11xcex2-(4-acetylphenyl)-17xcex2-hydroxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)estra-4,9,15-trien-3-one;
4xe2x80x2-[17xcex2-hydroxy-3-oxo-17xcex1-(1,1,2,2,2-pentafluoroethyl)estra-4,9,15-trien-11xcex2-yl][1,1xe2x80x2-biphenyl]-4-carbonitrile;
11xcex2-(4xe2x80x2-fluoro[1,1xe2x80x2-biphenyl]-4-yl)-17xcex2-hydroxy-17xcex1-(1,1,2,2,2-pentafluoroethyl))estra-4,9,15-trien-3-one;
17xcex2-hydroxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)-11xcex2-[4-(3-pyridinyl)phenyl]estra-4,9,15-trien-3-one;
6xe2x80x2-acetyl-9,11xcex1-dihydro-17xcex2-hydroxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)-4xe2x80x2H-naphth[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-3-one;
4-[9,11xcex1-dihydro-17xcex2-hydroxy-3-oxo-17xcex1-(1,1,2,2,2-pentafluoroethyl)-4xe2x80x2H-naphth[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-6xe2x80x2-yl]benzonitrile;
9,11xcex1-dihydro-6xe2x80x2-(4-fluorophenyl)-17xcex2-hydroxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)-4xe2x80x2H-naphth[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-3-one;
9,11xcex1-dihydro-17xcex2-hydroxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)-6xe2x80x2-(3-pyridinyl)-4xe2x80x2H-naphth[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-3-one;
6xe2x80x2-acetyl-9,11xcex1-dihydro-17xcex2-hydroxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)-4xe2x80x2H-naphth[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estra-4,15-dien-3-one;
4-[9,11xcex1-dihydro-17xcex2-hydroxy-3-oxo-17xcex1-(1,1,2,2,2-pentafluoroethyl)-4xe2x80x2H-naphth[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estra-4,15-dien-6xe2x80x2-yl]be
9,11xcex1-dihydro-6xe2x80x2-(4-fluorophenyl)-17xcex2-hydroxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)-4xe2x80x2H-naphth[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estra-4,15-dien-3-one;
9,11xcex1-dihydro-17xcex2-hydroxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)-6xe2x80x2-(3-pyridinyl)-4xe2x80x2H-naphth[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estra-4,15-dien-3-one;
17xcex2-hydroxy-11xcex2-(4-hydroxyphenyl)-17xcex1-(1,1,2,2,2-pentafluoroethyl)estra-4,9-dien-3-one;
17xcex2-hydroxy-11xcex2-(4-hydroxyphenyl)-17xcex1-(1,1,2,2,2-pentafluoroethyl)estr-4-en-3-one;
9,11xcex1-dihydro-6xe2x80x2,17xcex2-dihydroxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)-4xe2x80x2H-naphth[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-3-one;
11xcex2-[4-(acetyloxy)phenyl]-17xcex2-hydroxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)estra-4,9-dien-3-one;
11xcex2-[4-(acetyloxy)phenyl]-17xcex2-hydroxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)estr-4-en-3-one;
6xe2x80x2-(acetyloxy)-9,11xcex1-dihydro-17xcex2-hydroxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)-4xe2x80x2H-naphth[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11estr-4-en-3-one;
17xcex2-hydroxy-11xcex2-[4-(hydroxymethyl)phenyl]-17xcex1-(1,1,2,2,2-pentafluoroethyl)estra-4,9-dien-3-one;
17xcex2-hydroxy-11xcex2-(4-(hydroxymethyl)phenyl]-17xcex1-(1,1,2,2,2-pentafluoroethyl)estr-4-en-3-one;
9,11xcex1-dihydro-17xcex2-hydroxy-6xe2x80x2-(hydroxymethyl)-17xcex1-(1,1,2,2,2-pentafluoroethyl)-4xe2x80x2H-naphth[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-3-one;
4-[17xcex2-hydroxy-3-oxo-17xcex1-(1,1,2,2,2-pentafluoroethyl)estra-4,9-dien-11xcex2-yl]benzaldehyde;
4-[17xcex2-hydroxy-3-oxo-17xcex1-(1,1,2,2,2-pentafluoroethyl)estr-4-en-11xcex2-yl]benzaldehyde;
9,11xcex1-dihydro-17xcex2-hydroxy-3-oxo-17xcex1-(1,1,2,2,2-pentafluoroethyl)-4xe2x80x2H-naphth[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-6xe2x80x2-al;
4-[17xcex2-hydroxy-3-oxo-17xcex1-(1,1,2,2,2-pentafluoroethyl)estra-4,9-dien-11xcex2-yl]benzoic acid methyl ester;
4-[17xcex2-hydroxy-3-oxo-17xcex1-(1,1,2,2,2-pentafluoroethyl)estr-4-en-11xcex2-yl]benzoic acid methyl ester;
9,11xcex1-dihydro-17xcex2-hydroxy-3-oxo-17xcex1-(1,1,2,2,2-pentafluoroethyl)-4xe2x80x2H-naphth[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-6xe2x80x2-carboxylic acid methyl ester;
17xcex2-hydroxy-11xcex2-[4-(1-hydroxyethyl)phenyl]-17xcex1-(1,1,2,2,2-pentafluoroethyl)estra-4,9-dien-3-one;
17xcex2-hydroxy-11xcex2-[4-(1-hydroxyethyl)phenyl]-17xcex1-(1,1,2,2,2-pentafluoroethyl)estr-4-en-3-one;
9,11xcex1-dihydro-17xcex2-hydroxy-6xe2x80x2-(1-hydroxyethyl)-17xcex1-(1,1,2,2,2-pentafluoroethyl)-4xe2x80x2H-naphth[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-3-one. 
The establishment of fluorinated side chains in the 17xcex1-position is carried out analogously to processes that have been described in many cases for other side chains by nucleophilic addition of an organometallic compound of formula MCnFmHo to a 17-ketone of general formula II, whereby M stands for a metal in the meaning of, e.g., Li, Na, K, Mg-halogen (halogen=Cl, Br, I) or other metals, and n, m and o have the meaning that is already indicated in general formula. I. To be preferred is the addition of Grignard reagents (CnFmHoMg-halogen) or the lithium-organic compounds such as LiCnFmHo. For the introduction of perfluorinated side chains, the generation of lithium-organic reagents starting from the corresponding iodides by means of a methyllithium/lithium bromide complex (J. Org. Chem. 1987, 52, 2481 and Tetrahedron Lett. 1985, 26, 5243) is especially suitable.
Substituents R1, R4, R5 and St that are mentioned in general formula II have the meanings that are already indicated in general formula I, whereby functional groups that are present in St optionally can be protected according to processes known to one skilled in the art. Especially carbonyl groups, such as, e.g., the 3-keto groupings, are protected in most cases in a suitable way, e.g., by the formation of a corresponding ketal or reduction to a hydroxy group, and optionally conversion of this hydroxy group into an ether or ester.
As a ketal protective group, for example, the ethylenedioxy or the 2,2-dimethlpropylene-1,3-dioxy group can be mentioned. Other standard keto protective groups are also considered. In the case of a protected hydtoxy group, the latter can be protected, for example, in the form of methoxymethyl, methoxyethyl, tetrahydroxypyranyl or silyl ether. By cleavage of the protective group and oxidation of the free hydroxy group, the keto group is obtained.
In a suitable stage after the 17xcex1-side chain has been added, the protective groups are then removed in a known way and optionally a hydroxy group is oxidized to the corresponding keto group.
The addition of the 17xcex1-side chain can also be carried out in a selective manner, however, in the presence of other free carbonyl groups, e.g., also the 3-keto group.
The startingmaterials of general formula II that are used for the production of the compounds of general formula I are described in a whole series of patents, patent applications and publications:
EP-A 0 057 115, EP-A 0 129 499, EP-A 0 259 2489, EP-A 0 186 834, EP-A 0 447 014, EP-A 0 116 974, EP-A 0 190 759, EP-A 0 147 361, EP-A 192 598, EP-A 0 283 428, EP-A 0 404 283, WO-A 89/00578, WO-A 91/18917, WO-A 91/18918, WO-A 92/11277, WO-A 92/11278, WO-A 93/23020, Steroids 44 (1984), 349 as well as other relevant bibliographic references that are known to one skilled in the art who is active in this field.
In the above-mentioned industrial-property rights, the introduction of radicals R4, R5, R6, R7 and R8, which occur there analogously to the radicals that are to be claimed here, is also described.
In general, the addition of the side chain with a free 17-keto group can be done at any intermediate stage in synthesis.
If the introduction of the fluorinated 17xcex1-alkyl side chain is carried out in an early synthesis intermediate stage, the establishment of additional radicals R6, R7 and R8 that are mentioned in St can be performed in the presence of this 17xcex1-side chain according to known processes, as they were described in, i.a., the above-mentioned patents, patent applications and publications.
The new compounds of general formula I are valuable pharmaceutical active ingredients. They are distinguished by a very strong antigestagenic activity. These are competitive progesterone antagonists, since they displace the progesterone from its receptor. At the same time, other endocrine side effects, such as, e.g., androgenic, estrogenic or antiglucocorticoidal activity are present if at all, only to a small extent. The compounds can therefore be used for medicinal purposes.
Compounds with antigestagenic activity (competitive progesterone antagonists) became known for the first time in 1982 (RU 486=EP-A 0 057 115) and have since been described extensively in, i.a., the already mentioned patent and bibliographic citations found.
Among the previously disclosed compounds, there are none with a multiply fluorinated 17xcex1-alkyl side chain that contains at least 2 carbon atoms. Onlycin WO83/03099 is it stated that the 3-keto-xcex944,9-19-nor steroids disclosed there can carry a 17xcex1-alkyl side chain, which optionally can be substituted with a halogen atom. Fluorine is not mentioned as a halogen. Concrete examples with a 17xcex1-alkyl chain that has at least 2 carbons previously did not exist at all.
Active ingredients of this type with strong antigestagenic activity are suitable for inducing abortions, since they displace from the receptor the progesterone that is necessary to maintain the pregnancy. They are therefore valuable and advantageous with respect to their use for postcoital birth control.
The compounds of general formula I according to the invention are also suitable for the production of preparations for female contraception (WO-A 93/23020, WO-A 93/21927).
In addition, they can be used to counteract hormonal irregularities, for triggering menstruation and for inducing labor. Other types of indications in the field of gynecology are the hormone replacement therapy (WO-A 94/18983), treatment of symptomr that accompany dysmenorrhea and endometriosis (EP-A 0 266 303) as well as myomas.
The compounds according to the invention exert strong antitumor activity in progesterone receptor positive rodent and human breat cancer models. Antiproliferative activity was observed in vitro in the human T47D breast cancer cell line. In vivo tumor inhibiting effects have been proven in the MXT-mammary carcinoma of the mouse and in the chemically induced mammary carcinoma models of the rat (NMU; N-nitroso methyl urea; DMBA: dimethylbenzanthracene.
The compounds according to the invention are thus highly suitable for the treatment of hormone-dependent carcinomas, for example, for treatment of the progesterone receptor positive mammary carcinoma. The compounds according to the invention can be used in the therapy of hormone dependent carcinomas for the first line therapy as well as for second line therapy, especially after tamoxifen failure.
The antigestagenically active compounds of general formula I according to the invention can also be used in combination with antiestrogenically active compounds for the production of pharmaceutical preparations for the treatment of hormone-dependent tumors (EP-A 0 310 542), for inducing labor, fork termination of pregnancy and for treatment of gynecological disorders (EP-A 0 310 541) and for female contraception (WO 96/19997). In the treatment of hormone dependent carcinoma, the antigestagen and the antiestrogen can be provided for simultaneous or even for sequential administration. In case of sequential treatment, it is preferred to administer first the antiestrogen and sequentially thereto the antigestagen.
Preferred antiestrogens include tamoxifen, the compounds of EP-A-138,504, especially 7xcex1-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]estra-1,3,5(10)-triene-3,17xcex2-diol, the compounds of U.S. Ser. No. 08/915,171 (PCT/EP97/04517), especially 11xcex2-fluoro-7xcex1-(14,14,15,15,15-pentafluoro-6-methyl-10-thia-6-azapentadecyl)-estra-1,3,5(10)-triene-3,17xcex2-diol, and aromatase inhibitors.
Amounts of antiestrogens are as indicated in the cited texts.
Examined as antigestagens were:
A: 11xcex2-(4-Acetylphenyl)-17xcex2-hydroxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)estr-4-en-3-one (Example 1)
B: 11xcex2-(4-Acetylphenyl)-17xcex2-hydroxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)estra-4,9-dien-3-one (Example 3)
C: 6xe2x80x2-Acetyl-9,11xcex1-dihydro-17xcex2-hydroxy-17xcex1-(1,1,2,2,2-pentafluoroethyl)-4xe2x80x2H-naphth[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-3-one (Example 5)
D: 11xcex2-[4-(Dimethylamino)phenyl]-17xcex2-hydroxy-17xcex1-(1-propinyl)estra-4,9-dien-3-one (RU 38 486)
E: 11xcex2-(4-Acetylphenyl)-19,24-dinor-17,23-epoxy-17xcex1-chola-4,9,20-trien-3-one (Org 33 628).
The tests below were all performed on rats according to known methods.
Abortive test s.c. and p.o.: See, for example, EP-A 0 283 428
Androgen test p.o.: Stimulation of the prostate weight with the test compound, vehicle: s.c. benzylbenzoate, castor oil (1+4); p.o. NaCl-myrj; reference compound testosterone propionate. Virtually no stimulation of the prostate weight is observed up to a dose of 10 mg of test compound/animal/day.
Uterus growth test p.o. for estrogenic action: Stimulation of uterus weight with the test compound, vehicle: s.c. benzylbenzoate/castor oil (1+4); p. o. NaCl-myrj; 3-day treatment of ovariectomized animals; parameters: uterus weight and endometrial epithelium height; vaginal smear negative; reference compound: estradiol 0.1 xcexcg.
Antithymolysis test p.o. on antiglucocorticoid action: See, for example, EP-A 0 283 428.
The invention thus also relates to pharmaceutical agents that are based on pharmaceutically compatible compounds of general formula I, i.e., compounds that are nontoxic in the doses used, optionally in connection with an antiestrogen together with commonly used adjuvants and vehicles.
Finally, this invention also relates to the use of compounds of general formula I, optionally together with an antiestrogen, for the production of pharmaceutical agents. The compounds according to the invention can be processed into pharmaceutical preparations for enteral, percutaneous, parenteral or local administration according to galenical methods that are known in the art. They can be administered in the form of tablets, coated tablets, gel capsules, granulates, suppositories, implants, injectable sterile aqueous or oily solutions, suspensions or emulsions, ointments, creams and gels or by means of intravaginal (e.g., vaginal rings) or intrauterine systems (pessaries, spirals).
The active ingredient or active ingredients can be mixed in this case with the adjuvants that are commonly used in galenicals, such as, e.g., gum arabic, talc, starch, mannitol, methyl cellulose, lactose, surfactants such as Tweens or Myrj, magnesium stearate, aqueous or ion-aqueous vehicles, paraffin derivatives, wetting agents, dispersing agents, emulsifiers, preservatives and flavoring substances for taste correction (e.g., ethereal oils).
A dosage unit contains, e.g., about 0.1-100 mg of active ingredient(s). The dosage of the compounds according to the invention is approximately 0.1-400 mg per day in humans. Particular dosages in a given patient can be determined routinely, e.g., considering the usual factors such as patient condition, age, weight, etc. Administration of the compounds is analogous to that of known antigestagens, e.g., RU 486.
The examples below are used to provide a more detailed explanation of this invention:
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius and unless otherwise indicated, all parts and percentages are by weight.
The entire disclosure of all applications, patents and pubiications, cited above and below, and of corresponding German application 197 06 061.7, filed Feb. 7, 1997, are hereby incorporated by reference.